Transdermal formulations

ABSTRACT

The present disclosure is directed to transdermal and moisturizing compositions.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Application No.PCT/US2015/000302, filed Dec. 23, 2015, which claims the benefit of U.S.Provisional Application No. 62/096,148, filed Dec. 23, 2014, theentireties of which are incorporated by reference herein.

BACKGROUND

Transdermal administration of therapeutic agents has many advantages,including convenience and gastrointestinal tract metabolism avoidance.But in the absence of penetration enhancing agents, many therapeuticagents are not capable of penetrating the skin in therapeuticallyeffective concentrations. As such, compositions that facilitate thepenetration of therapeutic agents through the skin are needed.

Also, the loss of skin moisture results in dry skin that can beuncomfortable, painful, or unattractive. Compositions that amelioratedry skin and increase or maintain skin hydration are also needed.

SUMMARY

The present disclosure is directed to compositions comprising a firstcomponent, a second component, a C₂₋₁₀alkyl alcohol, and an organic acidhaving 1 to 25 carbon atoms, wherein the first and second components arefurther defined herein. Methods of making and using these compositionsare also described.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The present disclosure may be understood more readily by reference tothe following detailed description of desired embodiments and theexamples included therein. In the following specification and the claimsthat follow, reference will be made to a number of terms which have thefollowing meanings.

As used in the specification and in the claims, the term “comprising”may include the embodiments “consisting of” and “consisting essentiallyof.” The terms “comprise(s),” “include(s),” “having,” “has,” “can,”“contain(s),” and variants thereof, as used herein, are intended to beopen-ended transitional phrases, terms, or words that require thepresence of the named ingredients/steps and permit the presence of otheringredients/steps. However, such description should be construed as alsodescribing compositions or processes as “consisting of” and “consistingessentially of” the enumerated ingredients/steps, which allows thepresence of only the named ingredients/steps, along with any impuritiesthat might result therefrom, and excludes other ingredients/steps.

Unless indicated to the contrary, the numerical values should beunderstood to include numerical values which are the same when reducedto the same number of significant figures and numerical values whichdiffer from the stated value by less than the experimental error ofconventional measurement technique of the type described in the presentapplication to determine the value.

All ranges disclosed herein are inclusive of the recited endpoint andindependently combinable (for example, the range of “from 2 to 10” isinclusive of the endpoints, 2 and 10, and all the intermediate values).The endpoints of the ranges and any values disclosed herein are notlimited to the precise range or value; they are sufficiently impreciseto include values approximating these ranges and/or values.

As used herein, approximating language may be applied to modify anyquantitative representation that may vary without resulting in a changein the basic function to which it is related. Accordingly, a valuemodified by a term or terms, such as “about” and “substantially,” maynot be limited to the precise value specified, in some cases. In atleast some instances, the approximating language may correspond to theprecision of an instrument for measuring the value. The modifier “about”should also be considered as disclosing the range defined by theabsolute values of the two endpoints. For example, the expression “fromabout 2 to about 4” also discloses the range “from 2 to 4.” The term“about” may refer to plus or minus 10% of the indicated number. Forexample, “about 10%” may indicate a range of 9% to 11%, and “about 1”may mean from 0.9-1.1. Other meanings of “about” may be apparent fromthe context, such as rounding off, so, for example “about 1” may alsomean from 0.5 to 1.4.

As used herein, “alkyl” refers to straight chain and branched chainshaving the indicated number of carbon atoms, usually from 1 to 20 carbonatoms, for example 1 to 8 carbon atoms, such as 1 to 6 or 1 to 7 carbonatoms. For example C₁₋₆ alkyl encompasses both straight and branchedchain alkyl of from 1 to 6 carbon atoms. When an alkyl residue having aspecific number of carbons is named, all branched and straight chainversions having that number of carbons are intended to be encompassed;thus, for example, “butyl” is meant to include n-butyl, sec-butyl,isobutyl and t-butyl; “propyl” includes n-propyl and isopropyl. Examplesof alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl,sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl,2-hexyl, 3-hexyl, 3-methylpentyl, and the like.

As used herein, “alkenyl” refers to an unsaturated branched orstraight-chain alkyl group having at least one carbon-carbon doublebond. The group may be in either the cis or trans configuration aboutthe double bond(s). The group may also be an aromatic group, forexample, a phenyl or phenylene moiety. Typical alkenyl groups include,but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl,prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl; butenyls such asbut-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl;phenylene, and the like. In certain embodiments, an alkenyl group hasfrom 2 to 20 carbon atoms.

As used herein, “alkynyl” refers to an unsaturated branched orstraight-chain alkyl group having at least one carbon-carbon triple bondderived by the removal of two molecules of hydrogen from adjacent carbonatoms of the parent alkyl. Typical alkynyl groups include, but are notlimited to, ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl;butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl; and thelike. In certain embodiments, an alkynyl group has from 2 to 20 carbonatoms.

The present disclosure is directed to compositions that moisturize theskin or that facilitate and/or enhance the transdermal permeation oftherapeutic agents through the skin. As used herein, “moisturize” refersto increasing hydration or preventing further hydration loss. As usedherein, the term “transdermal permeation” includes both percutaneousdelivery and transmucosal delivery, that is, passage through skin ormucosal tissue and into the bloodstream. As used herein in reference totransdermal penetration, the term “enhancing” refers to increasing therate at which a therapeutic agent penetrates the skin or mucosal tissueand enters the bloodstream. These compositions include a firstcomponent, a second component, an alcohol, an organic acid, and,optionally, water. Other compositions of the disclosure further comprisea therapeutic agent.

According to the disclosure, the first component comprises

-   -   a compound of formula I        R—(OCH₂CH₂)_(y)—OH   (I)        -   wherein R is C₁₋₂₀alkyl, C₂₋₂₀alkenyl; or C₂₋₂₀alkynyl; and            y is 1 to 25;    -   a tetrafunctional block copolymer surfactant terminating in        primary hydroxyl groups;    -   a sorbitan derivative;    -   a C₈₋₁₀alkyl ammonium salt;    -   a compound of formula II        HO—(CH₂CH₂O)_(m)—C(CH₃)(C₄H₉)—C≡C—C(CH₃)(C₄H₉)—(OCH₂CH₂)—OH  (II)        -   wherein m and n are each independently 1 to 25;    -   or a combination thereof.

In preferred embodiments of the disclosure, the first component is acompound of formula I. In some embodiments, R is C₁₋₂₀alkyl, which caneither be a straight chain or branched alkyl. Preferred compounds offormula I wherein R is C₁₋₂₀alkyl include, for example, is cetomacrogol1000; octadecan-1-ol, ethoxylated; polyoxyethylene(12)tridecyl ether;polyoxyethylene(10)tridecyl ether; fatty alcohol polyoxyethylene ether,polyoxyethylene branched nonylcyclohexyl ether (TRITON N-101),nonaethylene glycol monododecyl ether,23-{[4-(2,4,4-trimethyl-2-pentanyl)cyclohexyl]oxy}-3,6,9,12,15,18,21-heptaoxatricosan-1-ol,and combinations thereof. Nonaethylene glycol monododecyl ether isparticularly preferred.

In other embodiments, R is C₂₋₂₀alkenyl, which can either be a straightchain or branched alkenyl. Preferred compounds of formula I wherein R isC₂₋₂₀alkenyl include, for example, polyoxyl(10)oleyl ether, polyethyleneglycol tert-octylphenyl ether (TRITON X-100), and combinations thereof.

In yet other embodiment, R is C₂₋₂₀alkynyl, which can either be astraight chain or branch alkynyl.

In those embodiments wherein the first component is a compound offormula I, y is 1 to 25. In preferred embodiments, y is 5 to 15,preferably 8 to 10, with 9 being particularly preferred. In otherembodiments, y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, or 25.

In other aspects of the disclosure, the first component is atetrafunctional block copolymer surfactant terminating in primaryhydroxyl groups. Such compounds are commercially available under thetradename TETRONIC and includeethylenediaminetetrakis(ethoxylate-Block-propoxylate).

In other embodiments of the discosure, the first component is a sorbitanderivative, for example, polyoxyethylene sorbitan tetraoleate,1,4-anhydro-6-O-palmitoyl-D-glucitol (sorbitan, monohexadecanoate), apolyethylene glycol sorbitan monolaurate (e.g., TWEEN 20, TWEEN 40,TWEEN 60, TWEEN 85), and combinations thereof.

In still other embodiments of the disclosure, the first component is aC₈₋₁₀alkyl ammonium salt, for example, methyltrialkyl(C₈-C₁₀)ammoniumchloride (ADOGEN 464).

In other embodiments, the first component is a compound of formula II.

The compositions of the disclosure can comprise from about 0.1 vol. % toabout 40 vol. % of the first component. In preferred embodiments, thecompositions comprise from about 1 vol. % to about 40 vol. % of thefirst component. In other embodiments, the compositions comprise fromabout 0.1 vol. % to about 5 vol. % of the first component. For example,the compositions can comprise about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7,0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8,8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or about 40vol. % of the first component.

According to the disclosure, the compositions also include a secondcomponent that comprises

-   -   an compound of the formula III        R²—N(R¹)—C(O)—R³  (III)        -   wherein        -   each R¹ is independently H or C₁₋₃alkyl; and        -   R² and R³ are independently C₁₋₇alkyl or together with the            atoms to which they are attached, form a lactam having 3 to            10 carbon atoms,    -   a sulfoxide;    -   a urea;    -   ethyl acetate;

or a combination thereof

In preferred embodiments, the second component is compound of formulaIII. In some embodiments, R¹ is H. In other embodiments, R¹ is methyl,ethyl, propyl, or isopropyl, with methyl being particularly preferred.

In those embodiments wherein R² and R³ are independently C₁₋₇alkyl, eachof R² and R³ is independently methyl, ethyl, propyl, isopropyl, butyl,s-butyl, t-butyl, pentyl, hexyl, or heptyl.

Preferably, R² and R³, together with the atoms to which they areattached, form a lactam having 3 to 10 carbon atoms. For example, thelactam can include 3, 4, 5, 6, 7, 8, 9, or 10 carbons, which can be apart of the lactam ring or which can form exocyclic branching. Examplesof preferred lactams include pyrrolidones such as 2-pyrrolidone,1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone, and1-ethyl-2-pyrrolidone. Preferably, the lactam is1-methyl-2-pyrrolidinone or 2-pyrrolidone.

In some embodiments, the second component is a sulfoxide, for example,dimethyl sulfoxide.

In other embodiments, the second component is a urea, for example animidazolidinone.

The compositions of the disclosure can comprise from about 0.01 vol. %to about 10 vol. % of the second component. In preferred embodiments,the compositions comprise from about 0.01 vol. % to about 5 vol. % ofthe second component. In other embodiments, the compositions comprisefrom about 0.01 vol. % to about 4 vol. % of the second component. Forexample, the compositions can comprise about 0.01, 0.02, 0.03, 0.04,0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8,0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9,9.5, or about 10 vol. % of the second component.

In some embodiments of the disclosure, the ratio, by volume, of thefirst component to the second component is about 10:1 to about 4:1.

Alcohols for use in the compositions of the disclosure includeC₂₋₁₀alkyl alcohols having at least one —OH moiety or at least two —OHmoieties. For example, preferred alcohols include glycerol, propyleneglycol, ethanol, isopropanol, 1-propanol, butanol, t-butanol, pentanol,1-octanol, and combinations thereof, with ethanol being particularlypreferred.

The compositions of the disclosure can comprise from about 0.1 vol. % toabout 50 vol. % of the C₂-₁₀ alkyl alcohol. In preferred embodiments,the compositions comprise from about 1 vol. % to about 50 vol. % of theC₂₋₁₀ alkyl alcohol. In other embodiments, the compositions comprisefrom about 0.1 vol. % to about 5 vol. % of the C₂₋₁₀ alkyl alcohol. Forexample, the compositions can comprise about 0.1, 0.2, 0.3, 0.4, 0.5,0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7,7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,41, 42, 43, 44, 45, 46, 47, 48, 49, or about 50 vol. % of the C₂₋₁₀alkyl alcohol.

The compositions of the disclosure also include an organic acid having 1to 25 carbon atoms. For example, organic acids for use in the disclosecompositions include acetic acid, ascorbic acid, lactic acid, glycolicacid, propionic acid, and combinations thereof

Other organic acids for use in the disclosure include fatty acids. Asused herein, the term “fatty acid” has its ordinary meaning as would beunderstood by a person of ordinary skill in the art and includes amolecule having a carboxylic group and a hydrocarbon chain. Descriptionsof the number of carbon atoms in a fatty acid herein refer to the numberof carbon atoms in the hydrocarbon chain of the fatty acid, irrespectiveof whether the hydrocarbon chain is straight or branched.

As used herein, the term “fatty acid” includes saturated fatty acids,which do not contain any double or triple bonds in the hydrocarbonchain. Saturated fatty acids include, but are not limited to propionicacid (C3) (by way of example, C3 indicates propionic acid has 3 carbonatoms in its hydrocarbon chain; the number of carbon atoms in thehydrocarbon chain of other example fatty acids is denoted in analogousfashion herein), butyric acid (C4), valeric acid (C5), caproic acid(C6), enanthic acid (C7), caprylic acid (C8), pelargonic acid (C9),capric acid (C10), undecylic acid (C11), lauric acid (C12), tridecylicacid (C13), myristic acid (C14), pentadecylic acid (C15), palmitic acid(C16), margaric acid (C17), stearic acid (C18), isostearic acid (C18),nonadecylic acid (C19), arachidic acid (C20), heneicosylic acid (C21),behenic acid (C22), tricosylic acid (C23), lignoceric acid (C24),pentacosylic acid (C25), cerotic acid (C26), heptacosylic acid (C27),montanic acid (C28), nonacocylic acid (C29), melissic acid (C30),henatriacontylic acid (C31), lacceroic acid (C32), psyllic acid (C33),geddic acid (C34), ceroplastic acid (C35) and hexatriacontylic acid(C36).

As used herein, the term “fatty acid” also includes monounsaturatedfatty acids, which contain one double or triple bond in the hydrocarbonchain, and polyunsaturated fatty acids, which contain more than onedouble and/or triple bond in the hydrocarbon chain. Such acids include,but are not limited to the omega 3, omega 6, omega 9 fatty acids, otherfatty acids such as myristoleic and palmitoleic acid and conjugatedfatty acids. Examples of monounsaturated and polyunsaturated fatty acidsinclude but are not limited to, (a) omega 3 fatty acids, such ashexadecatrienoic acid (C16:3); (by way of example, C16:3 indicateshexadecatrienoic acid has 16 carbon atoms in its hydrocarbon chain and 3double bonds; the number of carbon atoms and double bonds in thehydrocarbon chain of other example unsaturated fatty acids is denoted inanalogous fashion herein), alpha linolenic acid (C18:3) andeicosapentanoic acid (20:5), (b) omega 6 fatty acids, such as linoleicacid (18:2), docosadienoic acid (C22:2), arachidonic acid (C20:4) andtetracosatetraenoic acid (C24:5), (c) omega 9 fatty acids, such as oleicacid (C18:1), eicosenoic acid (C20:1) and nevronic acid (C24:1), and (d)conjugated fatty acids such as rumenic acid (C18:2), eleostatic acid(C18:3), and rumelenic acid (C18:3).

As used herein, the term “fatty acid” also includes branched fattyacids. Examples of branched fatty acids include, but are not limited to,monomethyl branched fatty acids, such as 14-methyl pentadecanoic acid,6-methyl caprylic acid, 4-methyl-3-pentenoic acid, (pyroterebic acid),2-methyl-2E-butenoic acid (tiglic acid), 2-methyl-2Z-butenoic acid(angelic acid), multimethyl branched acids, isoprenoid fatty acids(vittatalactone, all-trans-retinoic acid), branched methoxy fatty acidsand hydroxy and other fatty acids such as 2-hydroxyoctanoic acid and4-oxopentanoic acid.

The compositions of the disclosure can comprise from about 0.01 vol. %to about 15 vol. % of the organic acid. In some embodiment, thecompositions comprise from about 1 vol % to about 15 vol % of theorganic acid. In preferred embodiments, the compositions comprise fromabout 0.01 vol. % to about 5 vol. % of the organic acid. In otherembodiments, the compositions comprise from about 0.01 vol. % to about 3vol. % of the organic acid. For example, the compositions can compriseabout 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2,0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5,5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13,13.5, 14, 14.5, or about 15 vol. % of the organic acid.

Compositions of the disclosure can be anhydrous. As used herein,“anhydrous” refers to compositions comprising less than 1 vol. % ofwater, preferably less than 0.05 vol. % or less than 0.025 vol. % ofwater. Methods of determining water content are known in the art.

Compositions of the disclosure can include water. In some embodiments,the compositions can comprise up to 99 vol. % of water. In still otheraspects, the compositions can comprise 5, 10, 20, 30, 40, 50, 60, 70,80, 90, 95, or 99 vol. % of water. In other embodiments, thecompositions can comprise 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 vol.% of water.

Compositions of the disclosure that include water can optionally containone or more physiologically acceptable salts. While not being bound byany particular theory, it is believed that controlling the amount ofsalt that is present allows one to control the depth to which thepresent composition penetrate skin, with the concentration of salthaving a generally inverse relationship to the penetration depth. Saltsfor use in the compositions include, but are not limited to, sodiumchloride, potassium chloride, and mixtures thereof. A preferred form ofsodium chloride is bacteriostatic sodium chloride solution.

The compositions of the disclosure can also include a therapeutic agent.As used herein, the term “therapeutic agent” refers to a compound that,upon administration to a patient in a therapeutically effective amount,provides a therapeutic benefit to the patient. A therapeutic agent maybe referred to herein as a drug or biologic. Those skilled in the artwill appreciate that the term “therapeutic agent” is not limited todrugs or biologics, or to materials that have received regulatoryapproval.

For example, such therapeutic agents include, but are not limited to,hormones such as estrogens, progestins, and androgens for both male andfemale health, adrenocortical steroids and their synthetic analogs forinflammation and/or various manifestations of adrenal insufficiency orpituitary hormone excess, antinausea/antiemetic drugs, tricyclicantidepressants, migraine and other pain drugs including NSAIDs andnarcotics, hypnotics, some beta blockers, alpha blockers, neuromuscularblocking agents, diuretics, antimalarial drugs, dermatologicals,antimetabolites, peptides such as leuprolide, goserelin or histrelin. Inother embodiments the therapeutic agent may be, but is not limited to,an agent to treat Alzheimer's, an anabolic agent, an analgesic agent, ananesthetic agent, an antacid, an anti-asthmatic agent, ananticholesterolemic agent, an anti-lipid agent, an anti-coagulant, ananti-convulsant, an anti-diarrheal, an antiemetic, an anti-inflammatoryagent, an antifungal agent, an anti-manic agent, an anti-migraine, ananti-nauseant, a CNS anti-depressant, an antineoplastic agent, ananti-obesity agent, an anti-Parkinson's agent, an anti-pyretic agent, ananti-spasmodic agent, an anti-thrombotic agent, an anti-uricemic agent,an anti-anginal agent, an antihistamine, an anti-tussive, an appetitesuppressant, a biological, a cerebral dilator, a central nervous systemagent, a coronary dilator, a decongestant, a diuretic, an erythropoieticagent, an expectorant, a gastrointestinal sedative, a hormone or hormoneagonist or antagonist, an agent possessing mixed agonist and antagonistproperties on a hormone receptor, a hyperglycemic agent, a hypoglycemicagent, a prostaglandin or prostanoid, an estrogen or anti-estrogen, aprogestogen or anti-progestin, an androgen or anti-androgen, an opiateor opioid agonist or antagonist, a phenothiazine, a butyrophenone, abenzamide, a glucocorticoid, a dopamine antagonist, a hypnotic, ahypoglycemic agent, an ion exchange resin, a laxative, a mineralsupplement, a mucolytic agent, a neuromuscular drug, an NSAID, anoligonucleotide, an anti-Parkinson's agent, a peptide or polypeptide, aperipheral vasodilator, a psychotropic, a polynucleotide, a sedative, astimulant, a thyroid agent, an anti-thyroid agent, a uterine relaxant, acervical ripening agent, an agent for the induction of labor, a vitamin,a prodrug, or an agent that promotes healing.

Therapeutics also include benzoyl peroxide, salicylic acid, iodine, andoregano oil.

Specific examples of therapeutic agents suitable for use in compositionsof the invention include ropinirole, pramipexole, sumatriptan,zolmitriptan, rizatriptan, almotriptan, eletriptan, naratriptan,frovatriptan, zolpidem, zaleplon, eszopiclone, ramelteon, doxepin,ketoprofen, ketorolac, piroxicam, meloxicam, diclofenac, mifepristone,ulipristal, sildenafil, vardenafil, tadalafil, alprostadil, letrozole,anastrozole, oxycodone, hydrocodone, buprenorphine, fentanyl,sufentanyl, alfentanyl, morphine, naloxone, naltrexone, leuprolide,goserelin, histrelin, pyridoxine, doxylamine, dimenhydronate,diphenhydramine, meclizine, promethazine, prochlorperazine, droperidol,metaclopramide, haloperidol, prednisone, methylprednisolone, cortisol,thyrotropin, thyrotropin-releasing hormone, estradiol, progesterone,gonadotropin-releasing hormone, gonadotropin-releasing hormone agonistsor antagonists, and insulin.

Additional compounds suitable for use in compositions of the inventioninclude estrogens , which can be useful as contraceptives and/or hormonetherapies for menopause and other endocrine conditions. Suitableestrogens not mentioned elsewhere in this specification include ethinylestradiol and estradiol-17beta.

Additional compounds suitable for use in compositions of the inventioninclude progesterones and progestins, which can useful ascontraceptives, hormone therapies, or both, for menopause and otherendocrine conditions. Suitable progesterones and progestins notmentioned elsewhere in this specification include: Progesterone,Norgestimate, Norelgestromin (also called 17-deacetyl norgestimate),Norgestrel, Levo-norgestrel, Cyproterone Acetate, Gestodene,Desogestrel, Dienogest, Drosperinone, Norethindrone, and Norethindroneacetate.

Other compounds suitable for use in compositions of the inventioninclude anti-infectives. Suitable anti-infectives not mentionedelsewhere in this specification include Fenticonazole (base, nitrate orboth) and Fluconazole.

Additional compounds suitable for use in compositions of the inventioninclude nutritional supplements and vitamins. Suitable nutritionalsupplements and vitamins not mentioned elsewhere in this specificationinclude Calcium Carbonate, Cholecalciferol (a metabolite of Vitamin D),Folic Acid, Folate, and Metafolin.

Other compounds suitable for use in compositions of the inventioninclude compounds useful for treating central nervous system (CNS)disorders. Suitable compounds useful for treating central nervous system(CNS) disorders not mentioned elsewhere in this specification includeMethylphenidate (e.g., for ADHD), Paroxetine (base, mesylate salt, orboth), Valproic Acid, Lithium carbonate, Fentanyl, Lidocaine, andRivastigmine.

In preferred embodiments, a composition of the invention includes atherapeutic agent that is a serotonin receptor antagonist. Preferably,the serotonin receptor antagonist comprises a 5-HT₃ receptor antagonist.Even more preferably, the serotonin receptor antagonist is selected fromondansetron, dolasetron, granisetron, tropisetron, palonosetron, orsalts thereof.

Compositions of the invention may be designed to be administered to theskin or mucosal tissue of a patient in need of treatment. Compositionsof the invention may be formulated as gels, transdermal patches,lotions, creams, sprays, mists, emulsions, or dispersions. Appropriateexcipients for formulating a gel, transdermal patch, lotion, cream,spray, or mist are readily apparent to a person of skill in the art andinclude, but are not limited to, stabilizers, emulsifiers, thickeners,antimicrobials, humectants, propellants, spreading agents, polymers, andadhesives, such as pressure sensitive adhesives. In particular,excipients that may be used to form a transdermal gel include, but arenot limited to, alcohols, glycols, glycerin, butylated hydroxytoluene(BHT), and water.

Also within the scope of the disclosure are methods comprisingadministering any of the described compositions to the skin of a mammalfor a time and under conditions effective to achieve passage of at leasta portion of the composition through the skin. Skin permeation can bemeasured using techniques known in the art.

The compositions of the disclosure can be used to administer atherapeutic agent to a mammal. For example, in preferred embodiments,these methods comprise applying any of the described compositions to theskin of a mammal for a time sufficient to achieve permeation of at leasta portion of the therapeutic agent through the skin. Therapeutic agentskin permeation can be measured using techniques known in the art.

The compositions of the disclosure can be used in methods ofmoisturizing the skin. For example, these methods can comprisingidentifying on a mammal an area of skin having an undesirably low levelof moisture and applying any of the described compositions to the skin.Preferably, the level of moisture is increased or does not decrease.

The compositions described herein can be applied to any convenient skinsurface. Skin surfaces of interest include, but are not limited to:arms, leg, torso, head, neck, etc. The surface area that is covered bythe transdermal formulation following application is generallysufficient to provide for the desired amount of agent administration,and in certain embodiments ranges from about 1 cm² to about 200 cm².

The compositions described herein can be applied a single time or aplurality of times over a given time period, e.g., the course of thedisease condition being treated, where the dosing schedule when aplurality of patches are administered over a given time period may bedaily, weekly, biweekly, monthly, etc.

The compositions of the disclosure will, in some embodiments, include,in addition to the above-discussed components, one or more additionalcomponents. Additional components include, but are not limited to, atransdermal absorption enhancer, a preservative (e.g., paraben), anantioxidant, a stabilizing agent, a filling agent that contains ahydrophilic polymer; a cross-linking agents; and a plasticizing agent.

The following example is provided to illustrate the compositions,processes, and properties of the present disclosure. The example ismerely illustrative and not intended to limit the disclosure to thematerials, conditions, or process parameters set forth therein.

EXAMPLE Example 1 Moisturizing Composition

Nonaethylene glycol monododecyl ether (3 mL, 5.14 vol %),1-methyl-2-pyrrolidinone (0.3 mL, 0.515 vol. %), ethanol (4 mL, 6.86vol. %), oleic acid (1 mL, 1.72 vol. %), and water (50 mL, 85.8 vol. %)are combined to form an admixture. The resulting composition is appliedto an area of the skin that is dry or in need of moisture in order toalleviate symptoms of dry skin.

Example 2 Aqueous Composition for Transdermal Administration of aTherapeutic Agent

Nonaethylene glycol monododecyl ether (3 mL), 1-methyl-2-pyrrolidinone(0.3 mL), ethanol (4 mL), oleic acid (1 mL), and water (50 mL) arecombined to form an admixture. An effective amount of a therapeuticagent is combined with the admixture to form a transdermal composition.The transdermal composition is applied to the skin of a patient in anamount and for a time sufficient for the therapeutic agent to permeatethrough the skin and into the patient's bloodstream to achieve atherapeutic effect.

Example 3 Anhydrous Composition for Transdermal Administration of aTherapeutic Agent

Nonaethylene glycol monododecyl ether (3 mL), 1-methyl-2-pyrrolidinone(0.3 mL), ethanol (4 mL), and linoleic acid (1 mL) are combined to forman admixture. An effective amount of a therapeutic agent is combinedwith the admixture to form a transdermal composition.

Example 4 Transdermal Administration of a Therapeutic Agent Using anAnhydrous Composition

The transdermal composition of Example 3 is applied to the skin of apatient in an amount and for a time sufficient for the therapeutic agentto permeate through the skin and into the patient's bloodstream toachieve a therapeutic effect.

Example 5 Aqueous, Sensitive Tissue Transdermal Composition

The composition of Example 3 (1 mL) is mixed with 99 mL of water. Theresulting aqueous composition can be applied to a sensitive tissue, forexample a mucous membrane, for a time sufficient for the therapeuticagent to permeate through the sensitive tissue and into the patient'sbloodstream to achieve a therapeutic effect.

Example 6 Aqueous, Normal Skin Transdermal Composition

The composition of Example 3 (1 mL) is mixed with water 49 mL of water.The resulting aqueous composition can be applied to normal skin for atime sufficient for the therapeutic agent to permeate through the skinand into the patient's bloodstream to achieve a therapeutic effect.

Example 7 Aqueous, Insulin Transdermal Composition

Nonaethylene glycol monododecyl ether (3 mL), 1-methyl-2-pyrrolidinone(0.3 mL), ethanol (4 mL), and linoleic acid (1 mL) are combined. Insulin(3 mL, 100 units/mL, LANTUS SOLOSTAR, Sanofi) is then added to form anadmixture. The admixture (1 mL) is then combined with 24 mL of water.The resulting aqueous composition can be applied to skin or tissue for atime sufficient for the insulin to permeate through the skin or tissueand into the patient's bloodstream to achieve a therapeutic effect.

Example 8 Aqueous, Insulin Transdermal Composition

Nonaethylene glycol monododecyl ether (3 mL), 1-methyl-2-pyrrolidinone(0.3 mL), ethanol (4 mL), and linoleic acid (1 mL) are combined. Insulin(3 mL, 100 units/mL, LANTUS SOLOSTAR, Sanofi) is then added to form anadmixture. The admixture (1 mL) is then combined with 32.3 mL of water.The resulting aqueous composition can be applied to skin or tissue for atime sufficient for the insulin to permeate through the skin or tissueand into the patient's bloodstream to achieve a therapeutic effect.

What is claimed:
 1. A composition comprising nonaethylene glycolmonododecyl ether, 1-methyl-2-pyrrolidone, ethanol, linoleic acid, and atherapeutic agent that is insulin, wherein the composition allows forthe transdermal delivery of the therapeutic agent.
 2. The composition ofclaim 1, wherein the composition is anhydrous.
 3. The composition ofclaim 1, further comprising water.
 4. The composition of claim 1,wherein the ratio (v/v) of the nonaethylene glycol monododecyl ether tothe 1-methyl-2-pyrrolidone is from 9:1 to 11:1.
 5. The composition ofclaim 1, further comprising an antimicrobial agent.
 6. The compositionof claim 4, wherein the ratio (v/v) of the nonaethylene glycolmonododecyl ether to the 1-methyl-2-pyrrolidone is 10:1.
 7. A methodcomprising applying a composition of claim 1 to the skin or a mucousmembrane of a mammal for a time sufficient to achieve permeation of atleast a portion of the therapeutic agent through the skin or the mucousmembrane.